Relationship of Brain Phosphate Metabolism and Cognition using 31 Phosphorus Magnetic Resonance Spectroscopy at 7-Tesla in Alzheimer's Disease




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Mitochondrial dysfunction, a neurometabolic marker, is considered an early marker in Alzheimer's disease (AD) that has speculated to precede toxic levels of amyloid and tau. Abnormal mitochondria function can negatively impact brain energy metabolism (BEM), oxidative and metabolic stress, leading to cell senescence and death. In-vitro cell line culture and postmortem AD studies suggest BEM abnormality, however have limited capability to capture the human brain's full complexity. Examining BEM in the in-vivo brain would confirm whether such abnormality is present and if so, to what extent, and how early it occurs in relation to the transitory stages of AD i.e., amnestic mild cognitive impairment (aMCI). The dissertation had three main goals. My first goal was to develop a methodology to measure BEM using advanced imaging technology such as 31-phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high-field (UHF) magnetic strength 7-T in human brain invivo. In the first phase, using partial volume-coil 31P MRS at 7-T over a brain region, i.e., parieto-occipital area, showed a well-separated high-resolution spectral display of thirteen metabolites signals, including energy phosphates and membrane phospholipid metabolites, in a single population of interest, i.e., aMCI. In my expanded research, I showed similar BEM data acquisition from the whole-brain volume-coil using same imaging technique. This work focused on three main energy phosphate metabolites-adenosine triphosphate (ATP), inorganic phosphate (Pi), and phosphocreatine (PCr). The measurements of these three metabolites were utilized to formulate three (3) BEM markers and two (2) regulatory co-factors [magnesium (Mg2+) and pH], including energy reserve index (PCr/t-ATP), energy consumption index (Pi/t-ATP), and metabolic state indicator (Pi/PCr). The next goal was to investigate if BEM markers and co-factors were significantly different across the three groups - cognitively normal (CN) (n=15), aMCI (n=15), and mild AD (n=11) in the four bilateral brain regions. The results showed that BEM markers was reduced in aMCI with further decrease in AD when compared to CN except metabolic state indicator. Interestingly, all the significant differences in BEM markers and regulatory co-factors were observed in the temporal region bilaterally, a vulnerable region where the AD pathology starts. The final goal was to study if the sensitive BEM markers and co-factors in the temporal lobe were associated with cognitive performance of memory, executive function (EF), attention, visuospatial skills, and language, respectively, across the groups. The findings showed a significant association of higher Mg2+ with improved memory, and EF in CN. On the other hand, in aMCI and mild AD, higher Mg2+ was related to lower performance in the same cognitive domains. Results suggest that in healthy brains, the Mg2+ supports the BEM mechanism, neuronal function and cognition. Whereas in aMCI and AD, the Mg2+ co-factor fails to support these systems. Overall, this work laid a foundation to investigate mitochondrial function using BEM in healthy and compromised brain in-vivo using novel and advanced imaging technology at UHF 7-T. Future work may explore ways to use this methodology using 31P MRS imaging technology to objectively measure the effectiveness of novel neurotherapeutics on mitochondrial function and dysfunction.



Brain -- Metabolism, Nuclear magnetic resonance spectroscopy, Adenosine triphosphate, Phosphocreatine